Heparin is a suflated polysaccharide mixture that is widely used as baseline therapy in a number of clinical situations, especially for preventing thrombosis. While heparin has been administered in the clinic for the past several decades, recently, clusters of serious allergic-type events were reported in patients undergoing hemodialysis who were receiving heparin causing a global health crisis. Within a matter of weeks from the time of this crisis, a multidisciplinary team that comprised of members from academia (including co-PIs of this proposal), FDA and industry identified an unnatural contaminant, over sulfated chondroitin sulfate (OSCS), in the heparin lots associated with the adverse reactions. Despite the fact that, in the last 20 years, a number of scientific studies identified analytical techniques, which have defined molecular level characteristics of heparin, including composition and sequence, this critical pharmaceutical agent was primarily controlled and dosed on the basis of activity, prior to this heparin crisis. Unfortunately, the activity assays have not been able to distinguish the heterogeneity arising from other sulfated polysaccharides that have been able to "hide behind" heparin. The solution to this crisis, therefore emphasizes the importance of incorporating more detailed analytical characterization to monitor and control the heterogeneity in heparins to avoid such a serious health crisis in the future. In this proposal we seek to structurally and functionally define heparin using a set of well developed and robust analytical and structure-function assays. The information on heparin obtained from these assays would enable us to construct filters for monitoring and controlling the quality of heparin. Finally we seek to develop an informatics platform to capture and disseminate the structural parameters that capture the macro- and microheterogeneity of heparin to compare them against well defined standards. The informatics platform would be critical to rapidly disseminate the findings from this proposal to improve current quality control measures for heparin. PUBLIC HEALTH RELEVANCE: The recent global health crisis due to contaminated lots of heparin has elevated the importance of measuring and controlling the structural heterogenetiy of complex polysaccharide drugs like heparin. In this proposal we seek to build on our experience and expertise in employing robust analytical methods to structurally and functionally define heparin.